zileuton extended release tablets / Generic mfg. - LARVOL DELTA

Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers. (PubMed, Cancers (Basel)) - "In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents."

Biomarker • Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Potential of pyrroquinazoline alkaloids from Adhatoda vasica Nees. as inhibitors of 5-LOX - a computational and an in-vitro study. (PubMed, J Biomol Struct Dyn) - "Molecular docking results indicated that these alkaloids have similar binding energy as that of Zileuton, a commercial drug...The in-vitro results indicate the potential of vasicinone as a competitive inhibitor, while the in-silico results highlighted the potential of vasicine and deoxyvasicine as allosteric inhibitors. A possible mechanism behind the activity exhibited by the plant was also determined, which emphasized the potential of these alkaloids as leads for the design of novel 5-LOX inhibitors."

Journal • Preclinical • Immunology • Inflammation

Asthma genomics and pharmacogenomics. (PubMed, Curr Opin Immunol) - "This includes 11 genome-wide association studies of asthma phenotypes that collectively identified 64 novel loci; transcriptome-wide asthma association studies which identified genes involved in virus recognition, bacterial infection, lung tissue remodeling, eosinophilic and neutrophilic inflammation and genes in the chromosome 17q12 asthma susceptibility locus; and three epigenome-wide studies of asthma that had robust sample sizes and replicated findings. We also highlight pharmacogenomic studies of corticosteroids, bronchodilator response to albuterol and zileuton, although finding from these studies may still be preliminary due to their relatively small sample sizes and limited availability of replication cohorts."

Biomarker • Journal • Review • Asthma • Immunology • Infectious Disease • Inflammation • Respiratory Diseases

Zileuton™ loaded in polymer micelles effectively reduce breast Cancer circulating tumor cells and intratumoral Cancer stem cells. (PubMed, Nanomedicine) - "Its great potential for CSCs treatment was subsequently demonstrated in in vitro and in in vivo CSC fluorescent models. Encapsulated Zileuton™ reduce amount of CSCs within the tumor and effectively block the circulating tumor cells (CTCs) in the blood stream and metastatic spread."

Cancer stem cells • Journal • Breast Cancer • Oncology • Solid Tumor

Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy. (PubMed, Sci Rep) - "Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon."

Journal

Zileuton ameliorates depressive-like behaviors, hippocampal neuroinflammation, apoptosis and synapse dysfunction in mice exposed to chronic mild stress. (PubMed, Int Immunopharmacol) - "More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN/BrdU cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression."

Journal • Preclinical • CNS Disorders • Depression • Immunology • Inflammation

New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition. (PubMed, Molecules) - "Zileuton's (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters' ester linkage and phenolic acid moieties were investigated. Unlike zileuton (1), Compound 28 formed two π-π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π-π interaction with Phe177 which may play a part in product specificity as reported."

Journal • Immunology • Inflammation

5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach. (PubMed, Bioorg Med Chem) - "Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades."

Journal • Review • Allergy • Asthma • Atherosclerosis • Cardiovascular • Dyslipidemia • Immunology • Inflammation • Respiratory Diseases

Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms. (PubMed, Biomedicines) - "The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways)."

Journal • Anesthesia • Corneal Abrasion • Dry Eye Disease • Immunology • Inflammation • Ocular Inflammation • Ophthalmology

In brief: Neuropsychiatric events with montelukast. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Allergic Rhinitis • Allergy • Asthma • Immunology • Psychiatry • Respiratory Diseases

A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes. (PubMed, Front Pharmacol) - "Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair)."

Journal • Acute Respiratory Distress Syndrome • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A cheminformatic study on chemical space characterization and diversity analysis of 5-LOX inhibitors. (PubMed, J Mol Graph Model) - "Due to the toxicity effect of FDA approved 5-LOX inhibitor zileuton, novel 5-LOX inhibitors have been sought by the scientific community...With the apparent exception of approved drugs, the 5-LOX dataset shows more diversity compared to FLAP and LOX virtual library set. This study was able to identify the underlying patterns in the chemical and pharmacological properties space that were decisive for the drug discovery and development of 5-LOX inhibitors."

Journal • Respiratory Diseases

High ability of zileuton ((±)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea) to stimulate I but suppress I and I independently of 5-lipoxygenase inhibition. (PubMed, Eur J Pharmacol) - "The elevation of BK channels caused by zileuton was also observed in hippocampal mHippoE-14 neurons, without any modification of single-channel amplitude. In conclusion, except for its suppression of 5-lipoxygenase, our results indicate that zileuton does not exclusively act on BK channels, and its inhibitory effects on I and I may combine to exert strong influence on the functional activities of electrically excitable cells in vivo."

Journal

Zileuton, a 5-Lipoxygenase Inhibitor, Exerts Anti-Angiogenic Effect by Inducing Apoptosis of HUVEC via BK Channel Activation. (PubMed, Cells) - "Additionally, zileuton suppressed the expression of VCAM-1, ICAM-1, ETS related gene (Erg) and the production of nitric oxide (NO). Taken together, our results show that zileuton prevents angiogenesis by activating the BK channel dependent-apoptotic pathway, thus highlighting its therapeutic capacity in angiogenesis-related diseases, such as cancer."

Journal • Oncology

Lupin Launches Zileuton Extended-Release Tablets (Lupin Pharmaceuticals Press Release) - "...Lupin Limited...announced the launch of Zileuton Extended-Release Tablets, 600 mg, having received an approval from the United States Food and Drug Administration (U.S. FDA) earlier...indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older."

Generic launch • Asthma • Respiratory Diseases

[VIRTUAL] Club Cell Protein-16 (CC16) Is Reduced in Hospitalized Chronic Obstructive Pulmonary Disease (COPD) Exacerbations (ATS-I 2020) - " We performed a case-control study (ratio 1:2, matched on age, sex, tobacco pack years, and FEV 1 % predicted) where hospitalized cases were individuals who participated in Zileuton to Treat Adults with Chronic Obstructive Pulmonary Disease (LEUKO) study. Matched controls were outpatients at high risk for AECOPD, but no exacerbations within the preceding 4 weeks, who participated in the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) study... Reduced plasma CC16 is associated with hospitalized AECOPD. Larger studies are needed to confirm our findings and future clinical trials are needed to evaluate the efficacy of CC16 as a novel treatment for COPD, especially in AECOPD."

Clinical • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core. (PubMed, Eur J Med Chem) - "In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC = 0.14 μM; reference inhibitor zileuton IC = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC = 4.50 and 2.46 μM, respectively). In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity."

Journal

Puerarin Exerts the Hepatoprotection from Chronic Alcohol-Induced Liver Injury via Inhibiting the Cyclooxygenase-2 and the 5-Lipoxygenase Pathway in Rats. (PubMed, Complement Med Res) - "The possible cytoprotective mechanisms of PR may be involved inhibition of the Cox-2 pathway and the 5-Lox pathway to suppress inflammatory response and regulate the protective factor PPAR-γ expression."

Journal • Preclinical • TNFA

Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management. (PubMed, J Allergy Clin Immunol Pract) - "Symptoms of MCAS and SM can be managed by blockade of mediator receptors (H1 and H2 antihistamines, leukotriene receptor blockade), inhibition of mediator synthesis (aspirin, zileuton), mediator release (sodium cromolyn), anti-IgE therapy, or a combination of these approaches. Acute episodes of mast cell activation require epinephrine, and prolonged episodes may be addressed with corticosteroids. Patients with clonal mast cell syndromes may need a reduction in the number of mast cells to prevent severe symptoms including anaphylaxis and/or progression to aggressive diseases."

Journal • Review • Aggressive Systemic Mastocytosis

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors. (PubMed, Arch Pharm (Weinheim)) - "All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy."

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Targeting Neutrophils for Enhanced Cancer Theranostics. (PubMed, Adv Mater) - "This design renders a greatly improved theranostic nanomedicine for efficient tumor suppression, and more importantly, inhibition of neutrophil-mediated lung metastasis via the sustained release of Zileuton. This work presents a novel strategy of targeting neutrophils for improved tumor theranostics, which may open up new avenues in designing nanomedicine through exploiting the tumor microenvironment."

Journal • Breast Cancer • Immunology • Lung Cancer • Oncology • Solid Tumor • MPO

Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors. (PubMed, J Enzyme Inhib Med Chem) - "Particularly, compounds PH-249 and PH-251 had outstanding potencies (IC < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced in vivo activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents."

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In vitro cytotoxicity of montelukast in HAPI and SH-SY5Y cells. (PubMed, Chem Biol Interact) - "The present study also compared the effects of montelukast with a 5-lipoxygenase inhibitor (zileuton) and a cyclooxygenase-2 inhibitor (celecoxib) to better understand modulation of related pathways. The results of the current study show the capability of montelukast to directly induce toxicity and inflammation in HAPI cells, possibly through the involvement of PGE and ROS, and toxicity in undifferentiated SH-SY5Y neuroblastoma cells. The current study highlights the importance of consideration between benefit and risk of montelukast usage and provides references for future investigation on decreasing montelukast-related NEs."

Journal • Preclinical • Asthma • Immunology • Neuroblastoma • Oncology • Respiratory Diseases • Solid Tumor

Extraction, Antioxidant Capacity, 5-Lipoxygenase Inhibition, and Phytochemical Composition of Propolis from Eastern Canada. (PubMed, Molecules) - "Extracts obtained with ethanol, methanol and acetone were effective free radical scavengers, and showed 5-LO inhibition similar to zileuton...Reversed-phase liquid chromatography tandem mass spectrometry confirmed the presence of 21 natural compounds in the propolis extracts based on the comparison of intact mass, chromatographic retention time and fragmentation patterns derived from commercial analytical standards. The current study is the first of its kind to concurrently investigate solvent polarity as well as extraction techniques of propolis."

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Pharmacological properties of novel LTC4 synthase inhibitor (ERS 2017) - "...AZD9898 is expected to inhibit the downstream production of CysLTs but, unlike the 5-LO inhibitor Zileuton, spare the production of LTB4 and the pro-resolving lipoxins... AZD9898 effectively inhibits CysLT production in vivo and in vitro and shows favorable pharmacological properties. LTC4 synthase may be the preferred point at to which inhibit cysteinyl leukotrienes in asthma patients and will be taken forward in clinical studies."

Asthma • Biosimilar • Immunology • Respiratory Diseases